SUMMARY HIV/AIDSremainsaformidableglobalepidemic,with~37millionpeopleinfected(including~1.1millionin the US) and about one million AIDS-related deaths in 2017 (UNAIDS, CDC). Despite the efficacy of modern combination anti-retroviral therapy (cART), side effects and drug resistance remain serious obstacles to achieving optimal care, and poor adherence is a key factor in treatment failure. Thus, there is continued demand for well-tolerated HIV inhibitors with novel mechanisms of action and stronger barriers to resistance. HIVspecialistsareespeciallyenthusiasticaboutthepotentialoflong-actingtherapiestominimizesideeffects, enhance efficacy, and delay resistance through improved compliance. Navigen has identified a novel, protease-resistantD-peptideHIVentryinhibitor,CPT31,withthesedesiredcharacteristicsandhasadvancedit throughpreclinicaldevelopment.CPT31addressesmanyofthelimitationsofcurrentcARTandhasprovento be well tolerated and highly efficacious for both indications in non-human primates (NHPs), making it an ideal candidate for both therapy and PrEP. Additionally, CPT31?s PK makes it amenable to monthly and perhaps quarterly dosing (with depot formulation). In this grant application, we will partner with Johns Hopkins University to conduct a Phase Ia/Ib safety, tolerability, pharmacokinetics, and pharmacodynamics study of CPT31. The study will include three stages: 1) single ascending dose (SAD) in healthy volunteers, 2) multiple ascendingdose(MAD)inhealthyvolunteers,and3)MADinHIVpositivepatientsclassifiedasGroup1under the FDA guidance for industry. This study will enable Navigen to determine whether CPT31 has the characteristicsthatwarrantcontinuedclinicalstudiesandfurtherinvestment.